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Diosmetin induces apoptosis and protective autophagy in human gastric cancer HGC-27 cells via the PI3K/Akt/FoxO1 and MAPK/JNK pathways

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Abstract

Gastric cancer represents a significant global health concern, necessitating the exploration of novel therapeutic options. Diosmetin, a natural flavonoid derived from citrus and vegetables, has demonstrated promising anti-tumor activity against various tumor cells. However, the potential anticancer effect of diosmetin in gastric cancer and its underlying mechanism have yet to be elucidated. In this study, we aimed to investigate the impact of diosmetin on cell proliferation, migration, cell cycle progression and apoptosis in human gastric cancer HGC-27 cells. Our findings revealed that diosmetin effectively suppressed cell proliferation, induced G2/M phase cell cycle arrest, and triggered cell apoptosis. Mechanistically, diosmetin downregulated the expression of antiapoptotic proteins Bcl-2 and Bcl-xL, while upregulated the level of proapoptotic proteins such as Bax, cleaved PARP and cleaved caspase-3. Additionally, diosmetin inhibited Akt and FoxO1 phosphorylation, while activated the MAPK signaling pathway. Notably, pretreatment of IGF-1, an Akt activator, attenuated the diosmetin-induced apoptosis. Furthermore, pretreatment with SP600125, a JNK inhibitor, significantly reduced the protein level of LC3B, while promoted the expression of cleaved caspase-3 and cleaved PARP. Collectively, our results suggest that diosmetin holds promise as an effective therapeutic agent against gastric cancer by inducing apoptosis through inhibition of the Akt/FoxO1 pathway and promoting protective autophagy via the MAPK/JNK signaling pathway.

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Abbreviations

HGC-27:

Human gastric cancer cell line

Bcl-2:

B-cell lymphoma 2

Bcl-xL:

B-cell lymphoma-extra large

Bax:

Bcl-2-associated X protein

PARP:

Poly (ADP-ribose) polymerases

Akt:

Protein kinase B

FoxO1:

Forkhead box protein O1

MAPK:

Mitogen-activated protein kinase

JNK:

Jun N-terminal kinase

LC3B:

Microtubule Associated Protein 1 Light Chain 3 Beta

GC:

Gastric cancer

MTS:

3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium

FBS:

Fetal bovine serum

PI:

propidium iodide

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine, iodide

DAPI:

4′,6-diamidino-2-phenylindole

TUNEL:

Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling

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Acknowledgements

This research was supported by the Competitive Allocation Project of Zhanjiang Municipal Science and Technology Development Special Fund (2021A05124 and 2022A01165).

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Author notes

  1. Zhaobin Pan and Zhiming Tan have contributed equally.

Authors and Affiliations

  1. Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, People’s Republic of China

    Zhaobin Pan, Zhiming Tan, Hongyan Li, Yang Wang, Haiyan Du, Jinhui Sun, Chunchao Li, Shicai Ye & Juanhua Quan

  2. Department of Respiratory Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang, 524045, Guangdong, People’s Republic of China

    Xin Li

  3. Laboratory of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, People’s Republic of China

    Juanhua Quan

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  1. Zhaobin Pan
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Pan, Z., Tan, Z., Li, H. et al. Diosmetin induces apoptosis and protective autophagy in human gastric cancer HGC-27 cells via the PI3K/Akt/FoxO1 and MAPK/JNK pathways. Med Oncol 40, 319 (2023). https://doi.org/10.1007/s12032-023-02180-w

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